Open Na+ channel blockade: multiple rest states revealed by channel interactions with disopyramide and quinidine

1994 ◽  
Vol 266 (5) ◽  
pp. H2007-H2017 ◽  
Author(s):  
Y. I. Zilberter ◽  
C. F. Starmer ◽  
A. O. Grant
Keyword(s):  
Steady State ◽  
Pulse Train ◽  
Pulse Amplitude ◽  
Direct Access ◽  
Na Channel ◽  
Channel Blockade ◽  
Atrial Myocytes ◽  
Channel Opening ◽  
Channel Interactions ◽  
Train Stimulation

In voltage-clamp studies of atrial myocytes exposed to disopyramide or quinidine, pulse-train stimulation revealed use-dependent block that increased with increased pulse amplitude. Use-dependent block also became negligible at hyperpolarized holding potentials (< -150 mV), consistent with either rapid unbinding at the holding potential or trapping of the drug in a drug-complexed rest conformation followed by rapid unbinding during the next channel opening event. To explore the unbinding properties of hypothetically different rest-blocked conformations, we exposed cells to a postdepolarization "conditioning" potential after channels had become fully inactivated so as to vary the transition to different hypothetical rest-blocked channels. Pulse-train stimulation from -130 to -30 mV generated only a small amount of use-dependent block. Inserting a 120-ms subthreshold (e.g., -100 mV) postdepolarization conditioning potential before return to -130 mV increased use-dependent block. The fraction of steady-state block exhibited a bell-shaped dependence on the conditioning potential. These results are consistent with the existence of a mixture of rest-blocked channel conformations, each having direct access to the blocked-inactivated state. These intermediate rest conformations display radically different drug unbinding rates.

Cardiac transient outward potassium current: a pulse chemistry model of frequency-dependent properties

1996 ◽  
Vol 270 (1) ◽  
pp. H386-H397
Author(s):  
L. Liu ◽  
V. I. Krinsky ◽  
A. O. Grant ◽  
C. F. Starmer
Keyword(s):  
Pulse Train ◽  
Outward Current ◽  
Drug Binding ◽  
Transient Outward Current ◽  
Channel Blockade ◽  
Frequency Dependent ◽  
Time Constants ◽  
Model Channel ◽  
Channel Interactions ◽  
Channel Availability

Recent voltage-clamp studies of isolated myocytes have demonstrated widespread occurrence of a transient outward current (I(to)) carried by potassium ions. In the canine ventricle, this current is well developed in epicardial cells but not in endocardial cells. The resultant spatial dispersion of refractoriness is potentially proarrhythmic and may be amplified by channel blockade. The inactivation and recovery time constants of this channel are in excess of several hundred milliseconds, and consequently channel availability is frequency dependent at physiological stimulation rates. When the time constants associated with transitions between different channel conformations are rapid relative to drug binding kinetics, the interactions between drugs and an ion channel can be approximated by a sequence of first-order reactions, in which binding occurs in pulses in response to pulse train stimulation (pulse chemistry). When channel conformation transition time constants do not meet this constraint, analytical characterizations of the drug-channel interaction must then be modified to reflect the channel time-dependent properties. Here we report that the rate and steady-state amount of frequency-dependent inactivation of I(to) are consistent with a generalization of the channel blockade model: channel availability is reduced in a pulsatile exponential pattern as the stimulation frequency is increased, and the rate of reduction is a linear function of the pulse train depolarizing and recovery intervals. I(to) was reduced in the presence of quinidine. After accounting for the use-dependent availability of I(to) channels, we found little evidence of an additional use-dependent component of block after exposure to quinidine, suggesting that quinidine reacts with both open and closed I(to) channels as though the binding site is continuously accessible. The model provides a useful tool for assessing drug-channel interactions when the reaction cannot be continuously monitored.

scholarly journals Kinetic analysis of the action of Leiurus scorpion alpha-toxin on ionic currents in myelinated nerve.

1985 ◽  
Vol 86 (5) ◽  
pp. 739-762 ◽  
Author(s):  
G K Wang ◽  
G Strichartz
Keyword(s):  
Steady State ◽  
Ionic Currents ◽  
Na Channel ◽  
Dependent Manner ◽  
Na Current ◽  
Toxin Concentration ◽  
Toxin Molecule ◽  
Channel Inactivation ◽  
Na Currents ◽  
Voltage Dependent

The effects of a neurotoxin, purified from the venom of the scorpion Leiurus quinquestriatus, on the ionic currents of toad single myelinated fibers were studied under voltage-clamp conditions. Unlike previous investigations using crude scorpion venom, purified Leiurus toxin II alpha at high concentrations (200-400 nM) did not affect the K currents, nor did it reduce the peak Na current in the early stages of treatment. The activation of the Na channel was unaffected by the toxin, the activation time course remained unchanged, and the peak Na current vs. voltage relationship was not altered. In contrast, Na channel inactivation was considerably slowed and became incomplete. As a result, a steady state Na current was maintained during prolonged depolarizations of several seconds. These steady state Na currents had a different voltage dependence from peak Na currents and appeared to result from the opening of previously inactivated Na channels. The opening kinetics of the steady state current were exponential and had rates approximately 100-fold slower than the normal activation processes described for transitions from the resting state to the open state. In addition, the dependence of the peak Na current on the potential of preceding conditioning pulses was also dramatically altered by toxin treatment; this parameter reached a minimal value near a membrane potential of -50 mV and then increased continuously to a "plateau" value at potentials greater than +50 mV. The amplitude of this plateau was dependent on toxin concentration, reaching a maximum value equal to approximately 50% of the peak current; voltage-dependent reversal of the toxin's action limits the amplitude of the plateauing effect. The measured plateau effect was half-maximum at a toxin concentration of 12 nM, a value quite similar to the concentration producing half of the maximum slowing of Na channel inactivation. The results of Hill plots for these actions suggest that one toxin molecule binds to one Na channel. Thus, the binding of a single toxin molecule probably both produces the steady state currents and slows the Na channel inactivation. We propose that Leiurus toxin inhibits the conversion of the open state to inactivated states in a voltage-dependent manner, and thereby permits a fraction of the total Na permeability to remain at membrane potentials where inactivation is normally complete.

scholarly journals Modification of a gas exchange system to measure active and passive chlorophyll fluorescence simultaneously under field conditions

AoB Plants ◽  
2020 ◽  
Author(s):  
Eliot W Meeker ◽  
Troy S Magney ◽  
Nicolas Bambach ◽  
Mina Momayyezi ◽  
Andrew J McElrone
Keyword(s):  
Chlorophyll Fluorescence ◽  
Steady State ◽  
Gas Exchange ◽  
Near Infrared ◽  
Pulse Amplitude ◽  
Bottom Plate ◽  
Pam Fluorometer ◽  
Promising Tool ◽  
Leaf Level ◽  
Gas Exchange System

Abstract Solar-induced fluorescence (SIF) is a promising tool to estimate photosynthesis across scales; however, there has been limited research done at the leaf-level to investigate the relationship between SIF and photosynthesis. To help bridge this gap, a LI-COR LI-6800 gas exchange instrument was modified with a visible-near-infrared (VIS-NIR) spectrometer to measure active and passive fluorescence simultaneously. The system was adapted by drilling a hole into the bottom plate of the leaf chamber and inserting a fiber-optic to measure passive steady-state fluorescence (Ft,λ, analogous to SIF) from the abaxial surface of a leaf. This new modification can concurrently measure gas exchange, passive fluorescence, and active fluorescence over the same leaf area and will allow researchers to measure leaf-level Ft,λ in the field to validate tower-based and satellite measurements. To test the modified instrument, measurements were performed on leaves of well-watered and water stressed walnut plants at three light-levels and a constant air temperature. Measurements on these same plants were also conducted using a similarly modified Walz GFS-3000 gas exchange instrument to compare results. We found a positive linear correlation between Ft,λ measurements from the modified LI-6800 and GFS-3000 instruments. We also report a positive linear relationship between Ft,λ and normalized steady-state chlorophyll fluorescence (Ft/Fo) from the pulse-amplitude modulation (PAM) fluorometer of the LI-6800 system. Accordingly, this modification will inform the link between spectrally resolved Ft,λ and gas-exchange – leading to improved interpretation of how remotely sensed SIF tracks changes in the light reactions of photosynthesis.

Cardiac instability amplified by use-dependent Na channel blockade

1992 ◽  
Vol 262 (4) ◽  
pp. H1305-H1310 ◽  
Author(s):  
C. F. Starmer ◽  
A. R. Lancaster ◽  
A. A. Lastra ◽  
A. O. Grant
Keyword(s):  
Sudden Death ◽  
Cardiac Arrhythmias ◽  
Tricyclic Antidepressants ◽  
Spatial Dispersion ◽  
Na Channel ◽  
Antiarrhythmic Agents ◽  
Channel Blockade ◽  
Vulnerable Period ◽  
Conditioning Stimuli ◽  
Increased Susceptibility

Drugs that exhibit use-dependent Na channel blockade, including antiarrhythmic agents, tricyclic antidepressants, opiate-like analgesics, and cocaine, are linked with an increased susceptibility to cardiac arrhythmias and sudden death. Computer simulations indicate that Na channel blockade retards recovery of excitability, thereby increasing the spatial dispersion of refractoriness, a precursor of many cardiac arrhythmias. In isolated rabbit left atria, stimuli timed to occur at increasing intervals following conditioning stimuli reveal an unstable interval (vulnerable period) during which single stimuli initiate trains of responses. The vulnerable period is extended by use-dependent Na channel blockade and provides a model for assaying proarrhythmic potential and probing cardiac instability.

scholarly journals Neuronal Na+ channel blockade suppresses arrhythmogenic diastolic Ca2+ release

2014 ◽  
Vol 106 (1) ◽  
pp. 143-152 ◽  
Author(s):  
Przemysław B. Radwański ◽  
Lucia Brunello ◽  
Rengasayee Veeraraghavan ◽  
Hsiang-Ting Ho ◽  
Qing Lou ◽  
...  
Keyword(s):  
Na Channel ◽  
Channel Blockade

Challenge for the in silico translation of Na channel blockade effects on human-ECG parameters

2019 ◽  
Vol 99 ◽  
pp. 106595
Author(s):  
Takashi Yoshinaga ◽  
Taeko Kubo ◽  
Keiichi Asakura ◽  
Yasuyuki Abe ◽  
Ryuuta Saitou ◽  
...  
Keyword(s):  
In Silico ◽  
Na Channel ◽  
Channel Blockade

The neuronal response to electrical constant-amplitude pulse train stimulation: additive Gaussian noise

2000 ◽  
Vol 149 (1-2) ◽  
pp. 129-137 ◽  
Author(s):  
A.J. Matsuoka ◽  
P.J. Abbas ◽  
J.T. Rubinstein ◽  
C.A. Miller
Keyword(s):  
Gaussian Noise ◽  
Pulse Train ◽  
Neuronal Response ◽  
Constant Amplitude ◽  
Train Stimulation

scholarly journals Kinetic and steady-state properties of Na+ channel and Ca2+ channel charge movements in ventricular myocytes of embryonic chick heart.

1992 ◽  
Vol 100 (2) ◽  
pp. 195-216 ◽  
Author(s):  
I R Josephson ◽  
N Sperelakis
Keyword(s):  
Steady State ◽  
Time Constant ◽  
Decay Time ◽  
Ventricular Myocytes ◽  
Ionic Currents ◽  
Decay Time Constant ◽  
Na Channel ◽  
Charge Movement ◽  
Embryonic Chick ◽  
Voltage Range

Nonlinear or asymmetric charge movement was recorded from single ventricular myocytes cultured from 17-d-old embryonic chick hearts using the whole-cell patch clamp method. The myocytes were exposed to the appropriate intracellular and extracellular solutions designed to block Na+, Ca2+, and K+ ionic currents. The linear components of the capacity and leakage currents during test voltage steps were eliminated by adding summed, hyperpolarizing control step currents. Upon depolarization from negative holding potentials the nonlinear charge movement was composed of two distinct and separable kinetic components. An early rapidly decaying component (decay time constant range: 0.12-0.50 ms) was significant at test potentials positive to -70 mV and displayed saturation above 0 mV (midpoint -35 mV; apparent valence 1.6 e-). The early ON charge was partially immobilized during brief (5 ms) depolarizing test steps and was more completely immobilized by the application of less negative holding potentials. A second slower-decaying component (decay time constant range: 0.88-3.7 ms) was activated at test potentials positive to -60 mV and showed saturation above +20 mV (midpoint -13 mV, apparent valence 1.9 e-). The second component of charge movement was immobilized by long duration (5 s) holding potentials, applied over a more positive voltage range than those that reduced the early component. The voltage dependencies for activation and inactivation of the Na+ and Ca2+ ionic currents were determined for myocytes in which these currents were not blocked. There was a positive correlation between the voltage dependence of activation and inactivation of the Na+ and Ca2+ ionic currents and the activation and immobilization of the fast and slow components of charge movement. These complementary kinetic and steady-state properties lead to the conclusion that the two components of charge movement are associated with the voltage-sensitive conformational changes that precede Na+ and Ca2+ channel openings.

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